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Open Access Publications from the University of California

GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP.

  • Author(s): Ramanan, Vijay K
  • Risacher, Shannon L
  • Nho, Kwangsik
  • Kim, Sungeun
  • Shen, Li
  • McDonald, Brenna C
  • Yoder, Karmen K
  • Hutchins, Gary D
  • West, John D
  • Tallman, Eileen F
  • Gao, Sujuan
  • Foroud, Tatiana M
  • Farlow, Martin R
  • De Jager, Philip L
  • Bennett, David A
  • Aisen, Paul S
  • Petersen, Ronald C
  • Jack, Clifford R
  • Toga, Arthur W
  • Green, Robert C
  • Jagust, William J
  • Weiner, Michael W
  • Saykin, Andrew J
  • Alzheimer’s Disease Neuroimaging Initiative (ADNI)
  • et al.

Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

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